This application is focused on capitalizing on our recent discovery that a carboxamido group (CONH2) can replace the phenolic OH of opioids and ameliorate the rapid clearance of opioids (e.g., duration of action increased from 2 to 15 hours) without compromising intrinsic affinity for opioid receptors or antinociception efficacy. Specifically, we will design, synthesize and characterize novel 8-carboxamido analogues of cyclazocine and ethylketocyclazocine (EKC) as potential anti-cocaine and anti- heroin medications. Cyclazocine is a k opioid agonist and a mu opioid antagonist and is currently in a clinical trial as a possible medication for cocaine abuse. Kappa agonists and mu antagonists decrease dopamine release in the nucleus acumens, a primary pathway involved in the reinforcing effects of drugs of abuse, and thus have the potential to treat drug abuse. EKC was shown to block cocaine self-administration in non-human primates. Therefore, derivatives of cyclazocine and EKC that do not have major side effects are potential medications for treating cocaine and heroin abuse in humans. We will also characterize novel carboxamido derivatives of other opioids (e.g., naltrindole, naltrexone) used as biochemical tools or for heroin abuse. Due to the uniqueness of this discovery, there is enormous potential to define a new SAR for opioids and we expect to identify new compounds having high affinity for opioid receptors. Taking advantage of computational techniques and our results with 8-aminocyclazocine analogues, we will probe an unexplored region of receptor space where an H-bond donor and hydrophobic group in the proper conformation are important for recognition. Based on the excellent preliminary pharmacokinetic and efficacy profile exhibited by these new carboxamides, we expect that the desired pharmacological profile will be attained by rational medicinal chemistry design and synthesis; an extensive pre-clinical work plan has been put in place. Radioligand binding, [35 S]GTP-gamma-S, and mouse antinociceptive assays will be used to characterize new targets pharmacologically.